Is MAPK12 p.Phe172Ile (c.514T>A) pathogenic?

MAPK12 p.Phe172Ile (c.514T>A) is classified Uncertain significance in MAPK12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-14). AlphaMissense: likely pathogenic (0.988); Absent from gnomAD v4.1.

How common is MAPK12 p.Phe172Ile (c.514T>A) in the general population?

MAPK12 p.Phe172Ile (c.514T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAPK12 p.Phe172Ile (c.514T>A)?

AlphaMissense predicts likely pathogenic (score 0.988) — an in-silico prediction, not a clinical call.

MAPK12 p.Phe172Ile

c.514T>A · VCV3870423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.988 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.988	likely pathogenic
REVEL	0.553	indeterminate
SaProt	LLR -13.96	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 8,105 bp · p 0.021 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAPK12
Protein: p.Phe172Ile
Coding: c.514T>A
MANE Select: NM_002969
Type: single nucleotide variant
Location: chr22:50256190 (GRCh38)
Gene constraint: LOEUF 1.387 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.33 · 4 PDB
Residue 172: the protein kinase domain

Full MAPK12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAPK12 p.Ala146Thr Uncertain significance ★ ⚠ same type
MAPK12 p.Ala175Val Uncertain significance ★ ⚠ same type
MAPK12 p.Ala296Thr Uncertain significance ★ ⚠ same type
MAPK12 p.Arg129Trp Uncertain significance ★ same type
MAPK12 p.Arg189Gln Uncertain significance ★ ⚠ same type
MAPK12 p.Arg189Trp Uncertain significance ★ ⚠ same type
MAPK12 p.Arg192Gln Uncertain significance ★ ⚠ same type
MAPK12 p.Arg192Trp Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mapk12-p-phe172ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown